P883: ALNUCTAMAB (ALNUC; BMS-986349; CC-93269), A BCMA × CD3 T-CELL ENGAGER, IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): LATEST RESULTS FROM A PHASE 1 FIRST-IN-HUMAN CLINICAL STUDY
Authors: Sandy W. Wong, Noffar Bar, María Victoria Mateos, Paz Ribas, Markus Hansson, Laura Paris, Craig Hofmeister, Paula Rodriguez-Otero, Maria Aranzazu Bermúdez, Armando Santoro, Andrew J. Yee, Maria Creignou, Cristina Encinas, Claudio Cerchione, Javier de la Rubia, Albert Oriol, Barbara Ferstl, Britta Besemer, Jinjie Chen, Alexander Chung, Isaac W. Boss, Allison Gaudy, Shaoyi LI, Kevin Hsu, Colin Godwin, Michael R. Burgess, Jesús San-Miguel, Luciano Jose Costa
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: ALNUC, a 2 + 1 T-cell engager (TCE) with bivalent binding to BCMA, has demonstrated clinical activity in pts with RRMM in an open-label phase 1 study (NCT03486067). IV-administered ALNUC exhibited a long duration of response (DOR) but resulted in cytokine release syndrome (CRS) in 76% of treated pts. Subcutaneous (SC) dosing reduced CRS rate and severity, allowing escalation to higher target doses, while showing promising antitumor activity. Aims: To present long-term follow-up data for IV ALNUC and safety and efficacy for SC ALNUC in pts with RRMM treated in the phase 1 study. Methods: Pts had ≥3 prior lines of therapy (LOTs), including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 therapy. IV ALNUC was administered at target doses of 0.15–10 mg with both fixed and step-up dosing as previously reported (Costa LJ et al. Blood 2019). SC ALNUC was given on d 1, 4, 8, 15, and 22 of cycle 1 (C1), QW in C2–3, Q2W in C4–6, and Q4W in C7 and beyond (28-d cycles). Step-up doses were given on C1D1 (3 mg) and C1D4 (6 mg), and target doses (≥10 mg) on C1D8 and thereafter. Safety and tolerability were primary objectives. Data cutoff was Nov 9, 2022. Results: In total, 70 pts had received IV ALNUC. Overall response rate (ORR) was 39% (27/70) with median DOR of 33.6 mo (95% CI, 10.6–NA). Median PFS was 3.1 mo (95% CI, 1.9–5.5). CRS was reported in 53 (76%) pts, with grade (G) ≥3 in 5 (7%) pts. Of 73 pts treated with SC ALNUC in dose escalation (target dose: 10 mg, 6; 15 mg, 4; 30 mg, 6; 60 mg, 7) and dose expansion (target dose: 10 mg, 19; 30 mg, 21; 60 mg, 10), median age was 64 y; 42% were female. Pts had a median of 4 prior regimens; 93% were refractory to last LOT, 100%/63% had triple-class exposed/refractory MM, and 66%/26% had penta-drug exposed/refractory MM. Median follow-up was 4.3 mo (range, 0.5–16.0); 39 (53%) pts were continuing treatment at data cutoff. Any-G/G3–4 treatment-emergent adverse events (TEAEs) occurred in 99%/79% of SC pts; most common were CRS (56%/0%), neutropenia (49%/42%), infections (47%/10%), anemia (41%/25%), and thrombocytopenia (33%/14%). All CRS events were G1 (44%; 32/73) or G2 (12%; 9/73); 35 (48%) pts received ≥1 concomitant medication for CRS, including tocilizumab (30%; 22/73) and/or corticosteroids (15%; 11/73). Median time to CRS was 3 d (range, 1–20); median duration was 2 d (range, 1–11). Two pts had G1 neurotoxicity suspected related to SC ALNUC. One pt discontinued treatment due to a TEAE (G3 metastatic colon cancer not suspected related to treatment); 1 treatment-related death (cerebral hemorrhage) occurred at the 60-mg target dose. Preliminary PK analysis of SC ALNUC estimated ~61% bioavailability with 15-d T½. Observed trough concentrations at the 30-mg target dose exceeded levels predicted for efficacy by C2D1. Hallmark pharmacodynamic effects of TCEs were observed with both SC and IV ALNUC. In 55 efficacy-evaluable pts treated with SC ALNUC, ORR was 53% across all doses and 65% at the 30-mg target dose (Figure). Among 29 pts who achieved a response, 16 of 20 pts with evaluable minimal residual disease (MRD) samples were MRD-negative (80%; 10-5 sensitivity by flow cytometry) at C2D1 or C4D1. Median time to response was 1.0 mo (95% CI, 0.7–1.3); 25 responses (86%) were ongoing. Summary/Conclusion: IV ALNUC continued to demonstrate durable responses in heavily pretreated pts with RRMM. SC administration improved the safety profile vs IV ALNUC, with CRS limited to low-grade, short-lived events. SC ALNUC exhibited promising dose-dependent antitumor activity and a high proportion of responders achieved MRD negativity. The phase 1 study is ongoing.E-Mail Address: Keywords: Subcutaneous, B-cell maturation antigen, Bispecific, Cytokine release syndrome